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Shedding Light on the Etiology of Male Breast Cancer

, by Victoria A. Fisher, M.P.H.

Scientists have long established female breast cancer as a heterogeneous disease composed of many different subtypes, each with specific features. Emerging evidence indicates that those unique subtypes not only respond differently to treatment, but also have distinct causes. Despite the complexity of this disease, researchers have been able to conduct robust studies of female breast cancer etiology, due in part to the number of available cases.

This tumor also occurs in men, but is relatively rare—men are diagnosed at less than one percent the rate of women. Until recently, much of our understanding of male breast cancer has been extrapolated from knowledge of female breast cancer. The few epidemiologic studies of male breast cancer have been limited in size and scope. Many have involved case-control designs, raising questions about the possibility of recall biases. Analyses of individual prospective studies have been difficult, given the small number of cases.

Louise Brinton

Recognizing the need for study on this rarer outcome, Louise A. Brinton, Ph.D., M.P.H., DCEG Scientific Advisor for International Activities, began work on this question in the mid-2000s. She utilized several large resources to describe a number of potential risk factors. Within the NIH-AARP Diet and Health Study, elevated risks were associated with a family history of breast cancer, obesity, physical inactivity, and a history of bone fractures (Brinton, 2008). In an additional study within the Veterans Administration, Dr. Brinton confirmed significant associations of male breast cancer with medical diagnoses of obesity, and extended findings to identify Klinefelter syndrome (a rare genetic condition), gynecomastia (excess breast tissue), and orchitis/epididymitis (testicle inflammation) as significant risk factors (Brinton, 2010).

From these individual studies, Dr. Brinton was able to identify patterns of risk. However, a larger study population was needed in order to expand upon these findings and identify new risk factors. To accomplish this, Dr. Brinton assembled an international collaborative effort with Michael B. Cook, Ph.D., and extramural colleagues to pool data from 21 studies, creating the Male Breast Cancer Pooling Project (MBCPP). They utilized both case-control and cohort studies, resulting in nearly 2,500 cases of this rare malignancy and 52,000 controls.

“By coordinating such a project, we were able to compile large numbers of cases for more robust analyses,” Dr. Brinton said. “Considerable effort was involved in harmonizing exposure data. In particular, we were interested in determining if hormonal risk factors applied to this cancer in men, as they do for women.”

Michael Cook

In 2014, Drs. Brinton and Cook published their first analyses from the MBCPP and confirmed that risk factors include obesity, Klinefelter syndrome, and gynecomastia (Brinton, Cook, 2014). Investigators observed a small but statistically significantly elevated risk for breast cancer in men with a high body mass index (BMI). Men with the highest BMI had a 35 percent greater risk of breast cancer compared to men with the lowest BMI. The elevated risk observed with men who have a high BMI (who often have excess breast tissue and elevated estrogen levels) appeared similar to the pattern for breast cancer risk in postmenopausal women. It was also determined that gynecomastia, independent from both Klinefelter syndrome and obesity, was associated with a 10-fold increased risk of male breast cancer.

“Similar to female breast cancer, these results seemed to support a role for hormonal factors in the etiology of male breast cancer,” Dr. Brinton said. “We therefore were interested in following up these findings to assess relationships with endogenous hormones.”

To further clarify the underlying mechanisms, Drs. Brinton and Cook measured estrogens and androgens in samples contributed by seven cohort studies within the MBCPP (Brinton, 2015). These analyses showed a significant association with increasing levels of estradiol. In contrast, androgens were not substantially related to risk, nor were ratios of estrogens to androgens. These associations were not confounded or modified by other male breast cancer risk factors, including age or body mass.

Additional studies within the MBCPP have examined other potential factors related to risk. Neither alcohol consumption nor cigarette smoking appeared to be related (Cook, 2015) in a significant way. Although leisure-time physical activity has been consistently associated with a lower risk of postmenopausal female breast cancer, investigators found no evidence that physical activity conferred protection against male breast cancer (Arem, 2015).

“Thanks to Louise’s vision and tenacity with this effort, we’ve been able to generate really interesting, novel data,” Dr. Cook said. Analyses from the MBCPP have expanded knowledge of this poorly understood disease and have confirmed a strong hormonal etiology.

As a next step, Drs. Brinton and Cook plan to use the MBCPP as part of a collaborative effort to understand the germline genetics of male breast cancer. “We hope that our work in DCEG will continue to shed light on the etiology of this rare cancer,” Dr. Brinton said.

Related Publications

Brinton LA, Richesson DA, Gierach GL, et al. Prospective evaluation of risk factors for male breast cancer. J Natl Cancer Inst 2008;100:1477-1481

Brinton LA, Carreon JD, Gierach GL, et al. Etiologic factors for male breast cancer in the U.S. Veterans Affairs medical care system database. Breast Cancer Res Treat 2010;119:185-192

Brinton LA, Cook MB, McCormack V, et al. Anthropometric and hormonal risk factors for male breast cancer: Male breast cancer pooling project results. J Natl Cancer Inst 2014;106:djt465

Brinton LA, Key TJ, Kolonel LN, et al. Prediagnostic sex steroid hormones in relation to male breast cancer risk. J Clin Oncol 2015;33:2041-2050

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